WO2022116374A1 - 一种大麻素的微针制剂及其制备方法和应用 - Google Patents
一种大麻素的微针制剂及其制备方法和应用 Download PDFInfo
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- WO2022116374A1 WO2022116374A1 PCT/CN2021/072760 CN2021072760W WO2022116374A1 WO 2022116374 A1 WO2022116374 A1 WO 2022116374A1 CN 2021072760 W CN2021072760 W CN 2021072760W WO 2022116374 A1 WO2022116374 A1 WO 2022116374A1
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- microneedle
- polymer material
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- cannabidiol
- needle body
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
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- 239000006211 transdermal dosage form Substances 0.000 description 1
- YNIRKEZIDLCCMC-UHFFFAOYSA-K trisodium;phosphate;hydrate Chemical compound [OH-].[Na+].[Na+].[Na+].OP([O-])([O-])=O YNIRKEZIDLCCMC-UHFFFAOYSA-K 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
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Definitions
- the invention relates to the technical field of preparations, in particular to a microneedle preparation of cannabinoids (especially cannabidiol (CBD)) and a preparation method and application thereof.
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBC cannabidiol
- THC tetrahydrocannabinol
- THCV ⁇ 9-tetrahydrocannabinol
- CBD cannabidiol
- EPIDIOLEX anti-epileptic therapeutic effect
- cannabidiol due to the poor water solubility of cannabidiol, its oral bioavailability is low, oral administration is not the best route for treatment, and oral administration of cannabidiol has first-pass metabolism, so it is necessary to find alternative delivery methods
- the pathway bypasses the first-pass effect to achieve the therapeutic effect.
- the first-pass metabolism can be avoided by the transdermal route of administration, but the common transdermal dosage forms (ointments, creams, patches, etc.) are hindered by the stratum corneum and active epidermis, and the permeability is poor, making it difficult for cannabidiol to penetrate over the skin.
- the present invention provides a microneedle preparation, which comprises a microneedle base and a microneedle body vertically (connected) on the base, wherein the matrix material of the needle body is made of a polymer material,
- the needle body contains the active ingredient.
- the above-mentioned microneedles are soluble microneedles, and the matrix material of the needle body can be dissolved or degraded (partially or completely) in the skin.
- the above-mentioned active ingredients are uniformly dispersed in the matrix material of the needle body.
- the above-mentioned active ingredients include cannabinoids, for example, cannabidiol (CBD), cannabidiol (CBDV), cannabidiol (CBN), cannabidiol (CBG), cannabidiol (CBC), tetrahydrocannabinol Cannabidiol (THC), ⁇ 9-tetrahydrocannabinol (THCV) and pharmaceutically acceptable salts thereof, especially cannabidiol.
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD cannabidiol
- CBD can
- the amount of the active ingredient in the needle body is 0.01-80% (eg 0.01%, 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%) , 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%).
- the above-mentioned microneedle needles may be one or more, especially multiple, for example, the specification of the above-mentioned microneedle preparation may be 36-278 needles/cm 2 .
- the length of the above-mentioned needle body may be 100-1000 ⁇ m (for example, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 ⁇ m).
- the shape of the above-mentioned needle body may be a conical shape or a polyhedral pyramid (eg, a quadrangular pyramid).
- the above-mentioned polymer material is a water-soluble polymer material.
- the base material of the needle body is a natural polymer, such as monosaccharides and oligosaccharides (specifically, fructose, sucrose, maltose, trehalose, raffinose, etc.), polysaccharides (specifically, hyaluronic acid or its salt (eg sodium salt), sodium alginate, chondroitin sulfate, cellulose, chitosan, chitin, hydroxypropyl beta cyclodextrin, pullulan, glucan, etc. ), proteins (such as silk protein, collagen, gelatin, etc.).
- monosaccharides and oligosaccharides specifically, fructose, sucrose, maltose, trehalose, raffinose, etc.
- polysaccharides specifically, hyaluronic acid or its salt (eg sodium salt), sodium alginate, chondroitin sulfate, cellulose, chitosan, chitin,
- the matrix material of the needle body is a synthetic polymer, for example, povidone (PVP), polyvinyl alcohol (PVA), polylactic acid (PLA), polylactic acid-glycolic acid copolymer ( PLGA), polyethylene glycol (PEG), methyl vinyl ether-maleic anhydride copolymer, polyglycolic acid (PGA), carbomer (PAA), carboxymethyl cellulose (CMC).
- PVP povidone
- PVA polyvinyl alcohol
- PLA polylactic acid
- PLGA polylactic acid-glycolic acid copolymer
- PEG polyethylene glycol
- PGA methyl vinyl ether-maleic anhydride copolymer
- PAA carboxymethyl cellulose
- the molecular weight of the above polymer material is 1k-2000kDa (for example, 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 20k, 30k, 40k, 50k, 60k, 70k, 80k, 90k , 100k, 200k, 300k, 400k, 500k, 600k, 700k, 800k, 900k, 1000k, 2000kDa).
- 1k-2000kDa for example, 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 20k, 30k, 40k, 50k, 60k, 70k, 80k, 90k , 100k, 200k, 300k, 400k, 500k, 600k, 700k, 800k, 900k, 1000k, 2000kDa).
- the polymer material is povidone, such as povidone K30 and povidone K90.
- the polymer material is sodium hyaluronate.
- the molecular weight of the above-mentioned hyaluronic acid or its salt can be 1k-200kDa (eg 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 12k, 14k, 16k, 18k, 20k, 25k, 30k, 35k, 40k, 45k, 50k, 60k, 70k, 80k, 90k, 100k, 150k, 200kDa), especially 1-50kDa, 1-20kDa, 5-15kDa, 5-12kDa.
- 1k-200kDa eg 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 12k, 14k, 16k, 18k, 20k, 25k, 30k, 35k, 40k, 45k, 50k, 60k, 70k, 80k, 90k, 100k, 150k, 200kDa
- the molecular weight of the above-mentioned povidone can be 10k-2000k (for example, 10k, 20k, 30k, 40k, 50k, 60k, 70k, 80k, 90k, 100k, 200k, 300k, 400k, 500k, 600k, 700k, 800k, 900k, 1000k, 1200k, 1300k, 1400k, 1500k, 1600k, 1800k, 2000kDa), especially 10k-100kDa, 1000k-1500kDa.
- 10k-2000k for example, 10k, 20k, 30k, 40k, 50k, 60k, 70k, 80k, 90k, 100k, 200k, 300k, 400k, 500k, 600k, 700k, 800k, 900k, 1000k, 1200k, 1300k, 1400k, 1500k, 1600k, 1800k, 2000kDa
- 10k-100kDa, 1000k-1500kDa for example, 10k, 20k, 30k, 40k, 50
- the amount of the matrix material in the needle body is 0.1-99% (eg 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%) , 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
- the above-mentioned needles may also contain surfactants, such as polysorbate, polyoxyethylene castor oil, phospholipids, poloxamers, and the like.
- surfactants such as polysorbate, polyoxyethylene castor oil, phospholipids, poloxamers, and the like.
- the amount of the surfactant in the needle is 0.1-30% (for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7% %, 8%, 9%, 10%, 15%, 20%, 25%, 30%).
- the above-mentioned needle body may also contain other suitable pharmaceutically acceptable adjuvants, such as preservatives, moisturizing agents, absorption enhancers, and the like.
- the above-mentioned microneedle substrate may be made of a polymer material.
- the polymer material is a water-soluble polymer material, for example, fructose, sucrose, maltose, trehalose, raffinose, hyaluronic acid or its salt (such as sodium salt), sodium alginate, Chondroitin sulfate, cellulose, chitosan, chitin, hydroxypropyl beta cyclodextrin, pullulan, dextran, fibroin, collagen, gelatin, povidone (PVP), polyvinyl alcohol (PVA) ), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyethylene glycol (PEG), methyl vinyl ether-maleic anhydride copolymer, polyglycolic acid (PGA), carbomer (PAA), carboxymethyl cellulose (CMC), etc.
- a water-soluble polymer material for example, fructose, sucrose, maltose, trehalose, raffinose, hyalur
- the above-mentioned microneedle base is made of sodium hyaluronate.
- the molecular weight of hyaluronic acid or its salt can be 1k-200kDa (eg, 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 12k, 14k, 16k, 18k, 20k, 25k, 30k, 35k, 40k, 45k, 50k, 60k, 70k, 80k, 90k, 100k, 150k, 200kDa), especially 1-50kDa, 1-20kDa, 1-10kDa, 1 -5kDa.
- 1k-200kDa eg, 1k, 2k, 3k, 4k, 5k, 6k, 7k, 8k, 9k, 10k, 12k, 14k, 16k, 18k, 20k, 25k, 30k, 35k, 40k, 45k, 50k, 60k, 70k, 80k, 90k, 100k, 150k, 200kDa
- the macromolecular material in the microneedle body and the macromolecular material in the microneedle base may be the same or different.
- the above-mentioned microneedle preparation is a microneedle patch, which may further comprise an adhesive layer, a backing layer, and a release layer.
- the present invention also provides a method for preparing the above-mentioned microneedle preparation, which includes the step of adding a liquid containing a polymer material and an active ingredient into a microneedle mold.
- the above-mentioned preparation method comprises the following steps:
- step (2) adding the liquid obtained in step (1) into the microneedle mold and drying (to form a microneedle needle body);
- step (3) adding a solution of the second polymer material to the microneedle mold in step (2), and drying (to form a microneedle base).
- the liquid in step (1) can be in the form of a solution, a suspension, a melt, and the like.
- the solvent of the solution in step (1) is water or a volatile organic solvent (such as alcohol, specifically ethanol, propanol, etc.).
- the above-mentioned first polymer material is a water-soluble polymer material, such as fructose, sucrose, maltose, trehalose, raffinose, hyaluronic acid or its salt (eg, sodium salt), sodium alginate, chondroitin sulfate , cellulose, chitosan, chitin, hydroxypropyl beta cyclodextrin, pullulan, glucan, fibroin, collagen, gelatin, povidone (PVP), polyvinyl alcohol (PVA), poly Lactic acid (PLA), polylactic acid-co-glycolic acid (PLGA), polyethylene glycol (PEG), methyl vinyl ether-maleic anhydride copolymer, polyglycolic acid (PGA), carbomer (PAA) , carboxymethyl cellulose (CMC), etc.; in the embodiment of the present invention, the above-mentioned first polymer material is povidone (eg K30, K90),
- the above-mentioned second polymer material is a water-soluble polymer material, for example, fructose, sucrose, maltose, trehalose, raffinose, hyaluronic acid or its salt (such as sodium salt), sodium alginate, chondroitin sulfate , cellulose, chitosan, chitin, hydroxypropyl beta cyclodextrin, pullulan, glucan, silk protein, collagen, gelatin, povidone (PVP), polyvinyl alcohol (PVA), poly Lactic acid (PLA), polylactic acid-co-glycolic acid (PLGA), polyethylene glycol (PEG), methyl vinyl ether-maleic anhydride copolymer, polyglycolic acid (PGA), carbomer (PAA) , carboxymethyl cellulose (CMC), etc.; in the embodiment of the present invention, the above-mentioned second polymer material is hyaluronic acid or its salt (eg,
- first polymer material and the second polymer material may be the same or different.
- the content of the matrix material of the microneedle needle body is 1-50% (for example, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% by mass).
- the content of the active ingredient is 1-70% (for example, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% %, 50%, 55%, 60%, 65%, 70% by mass).
- the liquid in the above step (1) may also contain a surfactant, and the content of the surfactant may be 0.1-10% (for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7% %, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10% by mass).
- step (2) further includes realizing complete filling of the liquid in the mold by means of centrifugation, pressurization or vacuuming, and removing excess solution.
- the drying method of step (2) may be drying under blast conditions.
- the drying temperature of step (2) may be 30-45°C.
- step (1) includes: dissolving the first polymer material in a solvent, and then adding active ingredients to obtain a solution.
- the first polymer material is povidone (eg K30, K90).
- the solution of the first polymer material is 40%-60% (eg 40%, 45%, 50%, 55%, 60%) of povidone K30 in ethanol or 20%-40% (eg 20%, 25%, 30%, 35%, 40%) povidone K90 in ethanol.
- step (1) includes: respectively dissolving the first polymer material and the active ingredient in a solvent to obtain a solution of the first polymer material and a solution of the active ingredient, and then mixing the two solutions .
- the first polymer material is hyaluronic acid or its salt (eg, sodium salt).
- the solution of the first polymer material is 5%-25% (eg 5%, 10%, 15%, 20%, 25%) sodium hyaluronate (aqueous) solution.
- the solution of the second polymer material is 5%-50% (eg 5%, 10%, 20%, 30%, 40%, 50%) transparent Sodium phosphate (water) solution.
- the present invention also provides an application of the above-mentioned microneedle preparation in preparing a medicine for treating and/or preventing diseases.
- the above-mentioned diseases can be diseases that can be treated and/or prevented by the active ingredients in the microneedle preparation, for example, for cannabidiol
- the above-mentioned diseases can be depression, anxiety, pain, skin diseases, epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, tumors, diabetes, obesity, atherosclerosis, inflammation, liver damage, and more.
- the inventor has developed a microneedle formulation that can be directly administered intradermally, which has the dual advantages of injection administration and transdermal administration, and can greatly improve the transdermal rate and absorption of cannabinoids (such as cannabidiol). , effectively improve its oral medication defects, improve its bioavailability.
- This preparation form is also suitable for other cannabinoids with poor transdermal effect, and has broad application prospects and market value.
- Cannabinoid is a unique secondary metabolite in cannabis plants, and its structure mainly includes alkyl resorcinol or 3,5-dihydroxypentylbenzene and monoterpene moieties (for example, “Chang Li, Li Jianjun, Huang Siqi, etc.. Summary of research on plant cannabis active ingredients and their medicinal uses. Life Sciences. 2018, 38(2): 273-280”).
- cannabinoid as used herein includes the following substances: Cannabidiol (CBD), Cannabidiol (CBDV), Cannabidiol (CBN), Cannabidiol (CBG), Cannabidiol (CBC), Tetrahydro Cannabinol (THC), ⁇ 9-tetrahydrocannabinol (THCV), and the like, and pharmaceutically acceptable salts of these cannabinoid compounds, particularly poorly water-soluble or water-dispersible cannabinoids, such as cannabidiol.
- step 2) adding the solution in step 2) to step 1), adding 0.5 g of polysorbate 80, and stirring to suspend;
- the microneedle preparation was prepared by the melting method: 0.2 g of cannabidiol was evenly added to the surface of the microneedle mold, heated at 80 °C to make the cannabidiol in a molten state, and the melt was filled into the microneedles under vacuum conditions, and cooled to make the cannabidiol After solidification, 5% sodium hyaluronate (molecular weight of about 3000 Da) solution was added as a backing solution, and dried at 30-45° C. for 8 hours to obtain a cannabidiol microneedle preparation.
- the microneedles obtained in Examples 1-4 have a needle body length of 600 ⁇ m, a quadrangular pyramid shape, and a specification of 186 needles/square centimeter.
- the microneedle must have a certain mechanical strength to penetrate the stratum corneum of the skin during use.
- the mechanical strength of the microneedle was investigated by the aluminum foil puncture experiment. When puncturing the aluminum foil, the thumb presses the microneedle with a force of 5N to directly puncture a layer of aluminum foil (thickness: 10 ⁇ m). It was found that the cannabidiol microneedles prepared in Examples 2 and 3 could puncture four layers of aluminum foil, indicating that they had sufficient mechanical strength and met the experimental requirements. However, the cannabidiol microneedles prepared in Example 4 were easily broken and had poor mechanical strength.
- Trypan blue is a cell-active dye that cannot penetrate the stratum corneum, but can stain the inner tissue through the breakage of the stratum corneum, so the surface of the skin only appears blue dots where the microneedles penetrate.
- Transdermal test The in vitro permeation test was carried out by using a Franz horizontal diffusion cell (effective diffusion area 3.14 cm 2 ), and three tests were carried out in parallel, and 40% PEG 400 was used as the receiving medium. Magnetic stirring at 500 rpm was always maintained in the receiver cell.
- the microneedle preparations of Example 2 and Example 3 (respectively containing 30 mg CBD) were pressed with the thumb 5N to puncture the abdominal skin of the rat with the microneedle, keeping the closed state to prevent evaporation of the solution and change of ingredients.
- Injection volume 10 ⁇ L.
- Microneedle skin group (Example 2) 1040.00 ⁇ 20.94 143.68 ⁇ 5.56
- Microneedle skin group (Example 3) 727.48 ⁇ 23.76 99.19 ⁇ 4.81
- the 48-hour cumulative penetration amount of the microneedle skin group (Example 3) was 52.9 times that of the ointment skin group, and the average penetration rate of the microneedle skin group (Example 3) was 50.4 times that of the ointment skin group.
- the cumulative penetration of the microneedle group was significantly higher than that of the ointment group (P ⁇ 0.01).
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Abstract
一种大麻素的微针制剂及其制备方法和应用,特别是大麻二酚的微针制剂及其制备方法和应用。上述微针制剂为可溶性微针,其可直接用于皮内给药,具有注射给药和透皮给药的双重优势,可极大的提高大麻素(例如大麻二酚)的透皮速率和吸收量,有效地改善其口服用药缺陷,提高其生物利用度,具有广阔的应用前景和市场价值。
Description
本发明涉及制剂技术领域,具体涉及一种大麻素(特别是大麻二酚(CBD))的微针制剂及其制备方法和应用。
大麻中成分种类繁多,人们已从大麻中提取分离出上百种大麻素类物质,其中主要的包括大麻二酚(CBD)、次大麻二酚(CBDV)、大麻酚(CBN)、大麻萜酚(CBG)、大麻环萜酚(CBC)、四氢大麻酚(THC)、Δ9-四氢化次大麻酚(THCV)等。大麻二酚(CBD)作为不具有成瘾性的大麻素,其制剂研究较为广泛,且已有开发上市的具有抗癫痫治疗作用的药品(EPIDIOLEX);其在抗抑郁、抗焦虑、缓解疼痛、治疗皮肤病等治疗领域均有较多报道。
但是,由于大麻二酚水溶性较差,导致其口服生物利用度较低,口服给药并非用于治疗的最佳途径,且大麻二酚口服给药存在首过代谢,因此需要寻找替代的递送途径绕过首过效应来实现治疗效果。经皮给药途径即可避免首过代谢作用,但普通的经皮给药剂型(软膏、乳膏、贴剂等)受到角质层和活性表皮的共同阻碍,渗透性差,使大麻二酚难以透过皮肤。
发明内容
为克服现有技术的不足,本发明提供一种微针制剂,其包括微针基底和垂直(连接)于基底上的微针针体,其中,针体的基质材料由高分子材料制成,针体中包含活性成分。
具体地,上述微针为可溶性微针,针体的基质材料能够在皮肤中(部分或全部)溶解或降解。
具体地,上述活性成分均匀分散在针体的基质材料中。
具体地,上述活性成分包括大麻素,例如,大麻二酚(CBD)、次大麻二酚(CBDV)、大麻酚(CBN)、大麻萜酚(CBG)、大麻环萜酚(CBC)、四氢大麻酚(THC)、Δ9-四氢化次大麻酚(THCV)及其药学上可接受的盐,特别是大麻二酚。
具体地,以针体总质量计,针体中活性成分的量为0.01-80%(例如0.01%、0.1%、1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%)。
具体地,上述微针针体可以为一根或多根,特别是多根,例如上述微针制剂的规格可以为36-278针体/平方厘米。
具体地,上述针体的长度可以为100-1000μm(例如100、200、300、400、500、600、700、800、900、1000μm)。
具体地,上述针体的形状可以为圆锥形或多面锥形(如四棱锥形)。
具体地,对于针体的基质材料,上述高分子材料为水溶性高分子材料。
在本发明的一个实施方式中,针体的基质材料为天然高分子,例如,单糖类和寡糖类(具体如,果糖、蔗糖、麦芽糖、海藻糖、棉子糖等)、多糖类(具体如,透明质酸或其盐(例如钠盐)、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀粉、葡聚糖等)、蛋白类(具体如蚕丝蛋白、胶原蛋白、明胶等)。
在本发明的另一实施方式中,针体的基质材料为合成高分子,例如,聚维酮(PVP)、聚乙烯醇(PVA)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇(PEG)、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸(PGA)、卡波姆(PAA)、羧甲基纤维素(CMC)。
具体地,上述高分子材料的分子量为1k-2000kDa(例如1k、2k、3k、4k、5k、6k、7k、8k、9k、10k、20k、30k、40k、50k、60k、70k、80k、90k、100k、200k、300k、400k、500k、600k、700k、800k、900k、1000k、2000kDa)。
在本发明的一个实施例中,对于针体的基质材料,高分子材料为聚维酮,如聚维酮K30、聚维酮K90。
在本发明另一实施例中,对于针体的基质材料,高分子材料为透明质酸钠。
具体地,上述透明质酸或其盐(例如钠盐)的分子量可以为1k-200kDa(例如1k、2k、3k、4k、5k、6k、7k、8k、9k、10k、12k、14k、16k、18k、20k、25k、30k、35k、40k、45k、50k、60k、70k、80k、90k、100k、150k、200kDa),特别是1-50kDa,1-20kDa,5-15kDa,5-12kDa。
具体地,上述聚维酮的分子量可以为10k-2000k(例如10k、20k、30k、40k、50k、60k、70k、80k、90k、100k、200k、300k、400k、500k、600k、700k、800k、900k、1000k、1200k、1300k、1400k、1500k、1600k、1800k、2000kDa),特别是10k-100kDa、1000k-1500kDa。
具体地,以针体总质量计,针体中基质材料的量为0.1-99%(例如0.1%、1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)。
具体地,上述针体中还可以包含表面活性剂,例如,聚山梨酯、聚氧乙烯蓖麻油、磷脂、泊洛沙姆等。
具体地,以针体总质量计,针体中表面活性剂的量为0.1-30%(例如0.1%、0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%)。
具体地,上述针体中还可以包含其他适宜的药学上可接受的辅料,例如,防腐剂、保湿剂、吸收促进剂,等等。
具体地,上述微针基底可以由高分子材料制成。
具体地,对于上述微针基底,高分子材料为水溶性高分子材料,例如,果糖、蔗糖、麦芽糖、海藻糖、棉子糖、透明质酸或其盐(例如钠盐)、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀 粉、葡聚糖、蚕丝蛋白、胶原蛋白、明胶、聚维酮(PVP)、聚乙烯醇(PVA)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇(PEG)、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸(PGA)、卡波姆(PAA)、羧甲基纤维素(CMC)等。
在本发明的一个实施例中,上述微针基底由透明质酸钠制成。
具体地,对于微针基底,透明质酸或其盐(例如钠盐)的分子量可以为1k-200kDa(例如1k、2k、3k、4k、5k、6k、7k、8k、9k、10k、12k、14k、16k、18k、20k、25k、30k、35k、40k、45k、50k、60k、70k、80k、90k、100k、150k、200kDa),特别是1-50kDa,1-20kDa,1-10kDa,1-5kDa。
具体地,上述微针针体中的高分子材料与微针基底中的高分子材料可以相同或不同。
在本发明的一个实施方式中,上述微针制剂为微针贴片,其还可以包含粘胶层、背衬层、防粘层。
本发明还提供一种上述微针制剂的制备方法,其包括将包含高分子材料和活性成分的液体加入微针模具的步骤。
具体地,上述制备方法包括如下步骤:
(1)制备包含第一高分子材料和活性成分的液体;
(2)将步骤(1)所得液体加入微针模具中,干燥(形成微针针体);
(3)向步骤(2)的微针模具加入第二高分子材料的溶液,干燥(形成微针基底)。
具体地,步骤(1)中的液体可以为溶液、混悬液、熔融液等形式。
具体地,步骤(1)中溶液的溶剂为水或挥发类有机溶剂(如醇,具体如乙醇、丙醇等)。
具体地,上述第一高分子材料为水溶性高分子材料,例如,果糖、蔗糖、麦芽糖、海藻糖、棉子糖、透明质酸或其盐(例如钠盐)、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀粉、葡聚糖、 蚕丝蛋白、胶原蛋白、明胶、聚维酮(PVP)、聚乙烯醇(PVA)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇(PEG)、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸(PGA)、卡波姆(PAA)、羧甲基纤维素(CMC)等;在本发明的实施例中,上述第一高分子材料为聚维酮(例如K30、K90)、透明质酸或其盐(例如钠盐)。
具体地,上述第二高分子材料为水溶性高分子材料,例如,果糖、蔗糖、麦芽糖、海藻糖、棉子糖、透明质酸或其盐(例如钠盐)、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀粉、葡聚糖、蚕丝蛋白、胶原蛋白、明胶、聚维酮(PVP)、聚乙烯醇(PVA)、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚乙二醇(PEG)、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸(PGA)、卡波姆(PAA)、羧甲基纤维素(CMC)等;在本发明的实施例中,上述第二高分子材料为透明质酸或其盐(例如钠盐)。
具体地,上述第一高分子材料与第二高分子材料可以相同或不同。
具体地,步骤(1)的液体中,微针针体基质材料的含量为1-50%(例如1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%,按质量计)。
具体地,步骤(1)的液体中,活性成分的含量为1-70%(例如1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%,按质量计)。
具体地,上述步骤(1)的液体中还可以包含表面活性剂,表面活性剂的含量可以为0.1-10%(例如0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、2%、3%、4%、5%、10%,按质量计)。
具体地,步骤(2)还包括通过离心、加压或抽真空等方式实现液体在模具中的完全填充,除去多余溶液。
具体地,步骤(2)的干燥方式可以为鼓风条件下干燥。
具体地,步骤(2)的干燥温度可以为30-45℃。
在本发明的一个实施方式中,步骤(1)包括:将第一高分子材料溶于溶剂中,再加入活性成分,得到溶液。
具体地,上述步骤(1)中第一高分子材料为聚维酮(例如K30、K90)。
在本发明的一个实施例中,上述步骤(1)中,第一高分子材料的溶液为40%-60%(例如40%、45%、50%、55%、60%)的聚维酮K30的乙醇溶液或20%-40%(例如20%、25%、30%、35%、40%)的聚维酮K90的乙醇溶液。
在本发明另一实施方式中,步骤(1)包括:分别将第一高分子材料和活性成分溶于溶剂中,得到第一高分子材料的溶液和活性成分的溶液,然后将两种溶液混合。
具体地,上述步骤(1)中第一高分子材料为透明质酸或其盐(例如钠盐)。
在本发明的一个实施例中,上述步骤(1)中,第一高分子材料的溶液为5%-25%(例如5%、10%、15%、20%、25%)透明质酸钠(水)溶液。
在本发明的一个实施例中,步骤(3)中,第二高分子材料的溶液为5%-50%(例如5%、10%、20%、30%、40%、50%)的透明质酸钠(水)溶液。
本发明还提供一种上述微针制剂在制备治疗和/或预防疾病的药物中的应用。
具体地,上述疾病可以为微针制剂中的活性成分可以治疗和/或预防的疾病,例如,对于大麻二酚,上述疾病可以为抑郁、焦虑、疼痛、皮肤病、癫痫、多发性硬化症、帕金森病、阿尔茨海默症、肿瘤、糖尿病、肥胖、动脉粥样硬化、炎症、肝损伤等等。
发明人开发了一种可直接皮内给药的微针制剂,具有注射给药和透皮给药的双重优势,可极大的提高大麻素(例如大麻二酚)的透皮速率和吸收量, 有效地改善其口服用药缺陷,提高其生物利用度。此制剂形式同样适用于透皮效果较差的其他大麻素,具有广阔的应用前景和市场价值。
除非另有定义,本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
“大麻素”为大麻植株中特有的次生代谢产物,其结构主要包括烷基间苯二酚或3,5-二羟基戊苯和单萜部分(例如,“常丽,李建军,黄思齐等.植物大麻活性成分及其药用研究概括.生命的科学.2018,38(2):273-280”中所述)。本文中所用术语“大麻素”包括以下物质:大麻二酚(CBD)、次大麻二酚(CBDV)、大麻酚(CBN)、大麻萜酚(CBG)、大麻环萜酚(CBC)、四氢大麻酚(THC)、Δ9-四氢化次大麻酚(THCV)等以及这些大麻素化合物的药学上可接受的盐,特别是水溶性差或在水中分散性差的大麻素,例如大麻二酚。
本文所引用的各种出版物、专利和公开的专利说明书,其公开内容通过引用整体并入本文。
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
1)称取聚维酮(K30)10g,加入10g乙醇搅拌使溶解;
2)将大麻二酚20g加入到上述溶液中,加热使溶解,搅拌混匀备用;
3)将上述样品溶液加入到微针模具中,高速离心条件下使溶液完全填充到微针中;
4)置于30-45℃鼓风条件下干燥30分钟,向微针模具中加入5%的透明质 酸钠(分子量约为3000Da)溶液作为背衬溶液,继续干燥8小时,即得含大麻二酚的微针制剂。
实施例2
1)称取聚维酮(K90)30g,加入70g的乙醇搅拌使溶解;
2)将大麻二酚3.33g加入到上述溶液中,加热使溶解,搅拌混匀备用;
3)将上述的样品溶液加入到微针模具中,抽真空条件下使溶液完全填充到微针中;
4)置于30-45℃鼓风条件下干燥30分钟,向微针模具中加入5%的透明质酸钠(分子量约为3000Da)溶液作为背衬溶液,继续干燥8小时,即得含大麻二酚的微针制剂。
实施例3
1)称取10g的透明质酸钠(分子量约为9000Da),加入90g的纯化水,溶解后备用;
2)称取5g的乙醇溶液,加入5g的大麻二酚加热搅拌使溶解;
3)将步骤2)中的溶液加入到步骤1)中,加入0.5g的聚山梨酯80,搅拌使混悬;
4)将上述样品溶液加入到微针模具中,离心条件下使溶液完全填充到微针中;
5)置于30-45℃鼓风条件下干燥30分钟,向微针模具中加入5%的透明质酸钠(分子量约为3000Da)溶液作为背衬溶液,继续干燥8小时,即得含大麻二酚的微针制剂。
实施例4
采用熔融法制备微针制剂:将0.2g大麻二酚均匀加入微针模具表面,80℃下加热使大麻二酚呈熔融状态,真空条件下使熔融液填入微针中,冷却使大麻二酚凝固,加入5%的透明质酸钠(分子量约为3000Da)溶液作为背衬溶液,在30~45℃下干燥8小时,即得大麻二酚微针制剂。
实施例1-4所得微针,针体长度600μm,四棱锥形,规格为186针/平方厘米。
实施例5
大麻二酚微针的穿刺能力评价:
微针在使用过程中必须有一定的机械强度才能穿透皮肤角质层,通过铝箔穿刺实验对微针的机械强度进行了考察。铝箔穿刺时,拇指以5N的力按压微针直接穿刺一层铝箔(厚度:10μm),若顺利通过,则对折铝箔再次穿刺,以此类推。结果发现,实施例2和3制备的大麻二酚微针可穿刺4层铝箔,说明其具有足够的机械强度,符合实验要求。而实施例4制备的大麻二酚微针易折,机械强度较差。
实施例6
透皮性能试验:
取离体大鼠皮肤穿刺,拇指以5N的力按压微针(实施例2和3制备)穿刺健康无损伤大鼠离体皮肤,停留30s后,以医用胶布固定微针,10min后拔出微针,用0.4%台盼蓝溶液浸染皮肤表面,10min后除去皮肤表面的染色剂,观察皮肤表面染色小孔的情况。结果大鼠皮肤表面呈现出蓝色点状矩阵,与微针矩阵排列和间隔一致。台盼蓝是一种细胞活性染料,无法透过角质层,但可以通过角质层的破损处将内部组织染色,因此皮肤表面只有被微针穿透之处才能呈现出蓝色小点。实验后大鼠皮肤表面的蓝色点阵证明了大麻二酚微针可以成功的穿透大鼠皮肤。
实施例7
皮肤渗透试验:
1)离体皮肤制备:取健康大鼠,采用乙醚安乐死法处死大鼠,用剪刀剪去其腹部长毛后,用刀片小心刮净绒毛,迅速剥离其腹部皮肤,用脱脂棉擦除皮下脂肪及其他皮下组织,于-80℃下密封冷冻保存备用。
2)受试软膏制备:称取大麻二酚(CBD)10.0g、白凡士林70.0g、羊毛脂 20.0g,加热使熔融,搅拌至CBD溶解,放置室温后得到10%(g/g)的CBD软膏。
3)透皮试验:体外透过实验采用Franz横式扩散池(有效扩散面积3.14cm
2)进行,平行进行3次试验,采用40%PEG 400作为接收介质。接收池中始终保持500rpm磁力搅拌。分别将实施例2和实施例3的微针制剂(分别含30mg CBD),以拇指5N按压微针穿刺大鼠腹部皮肤,保持封闭状态防止溶液蒸发和成份改变。(另将10%(g/g)的CBD软膏制剂作为对照,均匀涂抹在相同大小的大鼠腹部皮肤上,作为软膏处理皮肤组,平行进行3次试验,均保持封闭状态防止溶液蒸发和成份改变)实验过程中于3、6、9、12、24、36、48h取样,在每个采样点取样后补充新鲜的接收液,以便在整个实验过程中皮肤的下表面始终保持与接受相的接触。利用高效液相色谱法考察接收液中药物含量,计算透皮吸收率。
4)检测方法:
色谱柱:Thermo OSD-2 HYPERSIL(4.6mm×150mm,5μm);
流动相:乙腈:水=70:30(v/v);
检测波长:220nm;
流速:0.8mL;
柱温:30℃;
进样量:10μL。
5)数据分析:
软膏中药物经半透膜的扩散遵循Higuchi公式,即药物(大麻二酚)累积释药量Q与时间t的平方根成正比。即Q=Kt
1/2,因此,斜率K可反应出软膏中药物释放的快慢。
表1 48h经皮渗透试验结果
组别 | Q/μg/cm 2 | K/μg/(cm 2·h) |
软膏皮肤组 | 13.74±0.46 | 1.97±0.04 |
微针皮肤组(实施例2) | 1040.00±20.94 | 143.68±5.56 |
微针皮肤组(实施例3) | 727.48±23.76 | 99.19±4.81 |
结果显示,48小时累积渗透量微针皮肤组(实施例2)是软膏皮肤组的75.7倍,微针皮肤组(实施例2)平均渗透速率是软膏皮肤组的72.9倍。48小时累积渗透量微针皮肤组(实施例3)是软膏皮肤组的52.9倍,微针皮肤组(实施例3)平均渗透速率是软膏皮肤组的50.4倍。微针组的累积渗透量均比软膏组有显著提高(P<0.01)。
通过透皮试验的数据可以看出上述微针制剂在透皮试验中具有明显优势。
表2实施例对比
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
Claims (10)
- 一种微针制剂,其包括微针基底和垂直于基底上的微针针体,其中,针体的基质材料由高分子材料制成,针体中包含活性成分;所述活性成分选自:大麻二酚、次大麻二酚、大麻酚、大麻萜酚、大麻环萜酚、四氢大麻酚、Δ9-四氢化次大麻酚及其药学上可接受的盐。
- 如权利要求1所述的微针制剂,其特征在于,对于针体的基质材料,所述高分子材料为水溶性高分子材料,优选自:果糖、蔗糖、麦芽糖、海藻糖、棉子糖、透明质酸或其盐、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀粉、葡聚糖、蚕丝蛋白、胶原蛋白、明胶、聚维酮、聚乙烯醇、聚乳酸、聚乳酸-羟基乙酸共聚物、聚乙二醇、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸、卡波姆、羧甲基纤维素中的一种或多种。
- 如权利要求1所述的微针制剂,其特征在于,对于针体的基质材料,所述高分子材料选自:聚维酮K30、聚维酮K90、透明质酸钠;优选地,所述透明质酸钠的分子量为5-15kDa。
- 如权利要求1所述的微针制剂,其特征在于,所述针体中还包含表面活性剂。
- 如权利要求1所述的微针制剂,其特征在于,所述微针基底由高分子材料制成,所述高分子材料为水溶性高分子材料,优选自:果糖、蔗糖、麦芽糖、海藻糖、棉子糖、透明质酸或其盐、海藻酸钠、硫酸软骨素、纤维素、壳聚糖、甲壳素、羟丙基β环糊精、支链淀粉、葡聚糖、蚕丝蛋白、胶原蛋白、明胶、聚维酮、聚乙烯醇、聚乳酸、聚乳酸-羟基乙酸共聚物、聚乙二醇、甲基乙烯基醚-顺丁烯酸酐共聚物、聚乙醇酸、卡波姆、羧甲基纤维素中的一种或多种;优选为透明质酸钠;优选地,所述透明质酸钠的分子量为1-10kDa。
- 如权利要求1所述的微针制剂,其特征在于,所述微针制剂为微针 贴片。
- 一种权利要求1-6任一项所述的微针制剂的制备方法,其包括将包含高分子材料和活性成分的液体加入微针模具的步骤。
- 如权利要求7所述的制备方法,其包括如下步骤:(1)制备包含第一高分子材料和活性成分的液体;(2)将步骤(1)所得液体加入微针模具中,干燥;(3)向步骤(2)的微针模具加入第二高分子材料的溶液,干燥。
- 如权利要求8所述的制备方法,其特征在于,步骤(1)包括:将第一高分子材料溶于溶剂中,再加入活性成分,得到溶液;其中,所述第一高分子材料为聚维酮K30或聚维酮K90;或,步骤(1)包括:分别将第一高分子材料和活性成分溶于溶剂中,得到第一高分子材料的溶液和活性成分的溶液,然后将两种溶液混合;其中,所述第一高分子材料为透明质酸钠。
- 一种权利要求1-6任一项所述的微针制剂在制备治疗和/或预防疾病的药物中的应用。
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